First, I propose to establish long-term lymphoblastoid cell lines (LCLs) from individuals with genetic disorders characterized by predisposition to cancer and/or hereditary tumors. This will be accomplished by transforming isolated blood leukocytes in vitro from affected individuals, using high titer Epstein-Barr virus (EBV). Secondly, I propose to study the in vitro sensitivity of these LCLs, as well as normal LCLs, to different chemical and physical mutagens. On a molecular level the amounts and types of DNA repair synthesis induced following exposure to DNA damaging agents will be quantitated for LCLs established from each disorder. In addition to these viability and repair studies, mutation frequencies for three different genetic markers will be examined in these LCLs following treatment with specific mutagenic agents. These studies will help identify those DNA damaging agents for which these individuals show increased sensitivity and which may increase their risk of developing cancer. The expected increased sensitivities of these same LCLs may also allow the identificaton of compounds that, following exposure, increase the risk of cancer for the general population as well. The proposed combined molecular and biological studies on repair replication and mutation frequencies will help us understand more fully the relationships between normal repair synthesis, defective repair synthesis and somatic cell mutation in mammalian cells.